Traditional chemical synthesis for drug discovery is done by individually creating, isolating, and identifying candidate compounds. Companies have long relied on their historical collections of compounds and compound collections from exchange agreements as sources of diverse structures for generating lead pharmaceutical compounds.
All of these historical approaches have drawbacks. Corporate collections of compounds may have a certain bias. Medicinal chemists using traditional synthetic techniques cannnot synthesize hundreds or thousands of diverse compounds to find promising leads.
Combinatorial chemistry is a relatively new technique for chemical synthesis. It fills the longfelt need for a method to quickly generate highly diverse non-peptide compound libraries. Generally, diverse libraries contain compounds with a common core or scaffold which are substituted with a great variety of substituents. More recently, modern drug discovery has used the methods of combinatorial chemistry to generate large numbers (viz., about 10.sup.2 to 10.sup.6) of compounds generically referred to as "libraries."
Combinatorial chemistry may be performed in a manner where libraries of compounds are generated as mixtures with complete identification of individual compounds postponed until after positive screening results are obtained. However, a preferred form of combinatorial chemistry is "parallel array synthesis" where individual reaction products (most often individual compounds) are synthesized together, but are retained in separate vessels. For example, the library compounds are held in the individual wells of 96 well microtiter plates. Use of standardized microtiter plates or equivalent apparatus is advantageous because such apparatus is readily manipulated by programmed robotic machinery.
Generally, combinatorial chemistry is conducted on a solid phase support, normally a polymer. A selected scaffold is cleavably tethered to the solid support by a chemical linker. Reactions are carried out to modify the scaffold while tethered to the solid support. In a final step, the product is cleaved and released from the solid support.
Combinatorial chemistry evidences its utility by commercial success. Millions of dollars have been spent for recent purchases or cooperative associations of major pharmaceutical companies with small companies specializing in combinatorial chemistry (e.g., Glaxo's acquisition of Affymax, Marion Merrell Dow's purchase of Selectide, Proctor & Gamble with Houghten, Astra with Alanex, Pfizer with Oxford Asymmetry, Sandoz with Pharmacopeia, Solvay with Arqule, CIBA with Chiron, and Eli Lilly with Sphinx Pharmaceutical).
Certain chemical reactions of thiophenes are known. The article, "Nucleophilic Substituition Reactions on Chlorinated Thiophene Derivatives as Basis for the Synthesis of Thienoanellated O,N-- and S,N-Heterocyclic" by Isolde Puschmann and Thomas Erker (Heterocyclis, Vol, 36, No. 6, 1993 pgs 1323-1332, 1993) describes nucleophilic substitution reactions of selected individual thiophenes.
To continue exploration of new libraries for pharmaceutical and agricultural lead compounds it is necessary to develop new chemistries which permit novel scaffolds to be functionalized with highly diverse groups.